1. Field of the Invention
The present invention relates to a novel salt of S-(−)-amlodipine, more specifically, to a nicotinic acid salt of S-(−)-amlodipine, a process for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient.
2. Description of the Related Art
Amlodipine, with a chemical name of 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicar boxylate, is a potent and long-acting calcium channel blocker useful as an anti-ischaemic and anti-hypertensive agent. It is known that the two enantiomers of amlodipine have different pharmacological profiles. The S-(−)-isomer is the more potent calcium channel blocker, while the R-(+)-isomer also exhibits activity in the treatment or prevention of atherosclerosis.
Although amlodipine is effective as a free base form, in practice, it is administered in a form of a pharmaceutically acceptable acid addition salt. Such a pharmaceutically acceptable salt of amlodipine must satisfy pharmaceutical characteristics, such as solubility, stability, non-hygroscopicity, processability for tablet formulation.
EP 89,167 and U.S. Pat. No. 4,572,909 disclose various pharmaceutically acceptable salt forms of amlodipine. For example, pharmaceutically acceptable acid addition salts are disclosed, formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts. Further, among them, maleate salt is disclosed as a preferable salt.
EP 244,944 and U.S. Pat. No. 4,879,303 disclose that benzene sulphonate salt of amlodipine (amlodipine besylate) has a number of advantageous physicochemical properties over the maleate salt thereof, such as good solubility, good stability, non-hygroscopicity, and processability for tablet formulation.
U.S. Pat. No. 6,291,490 discloses a method of treating a condition by excessive calcium influx in cells in a human, which comprises administering to said human in need of such therapy a therapeutically effective amount of (−) amlodipine, i.e., S-(−)-amlodipine or a pharmaceutically acceptable salt thereof. Further, U.S. Pat. No. 6,291,490 also discloses that such acid salt include acetic, benzene-sulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, and p-toluenesulfonic. And also, it discloses that particularly preferred are besylate, hydrobromic, hydrochloric, phosphoric and sulfuric acids.
However, according to the present inventors' experiments, the salts of S-(−)-amlodipine disclosed in the above, e.g., S-(−)-amlodipine besylate, do not have sufficient photostability.